Patchouli alcohol synthesis

Occasionally, however, things can go awry and examples exist in the chemical literature (albeit very few in number) of natural products whose structures, even after the "structure confirmation" by total synthesis, were shown to be incorrect in the light of the results obtained by X-ray crystallographic analysis. Patchouli alcohol, a natural sesquiterpene of some interest in the perfumery industry, provides an illuminating example. 

Previous work by Holton [15] on the synthesis of taxane ring systems, indicated that the preparation of the bicyclo[5.3.1]undecane skeleton lies basically on the work of Biichi on patchouli alcohol [16], which led him to the development of the so-called "epoxy alcohol fragmentation" [15a]. 

In an examination of the mechanism of the solvolysis of the tricyclic alcohol (627) which led to the successful synthesis of seychellene (628), Frater has shown that the minor product is the tricyclic olefin (629) which is formed by the process depicted in Scheme 79. An alternative synthesis of seychellene (628) and patchouli alcohol (635) depends upon the construction of the key tricyclic ketol (631) by an intramolecular Michael reaction followed by an aldol cyclization of (630) (Scheme 80). The minor ketol (632) can be converted into epi-sey-... 

A useful synthesis (ref.ll)of patchouli alcohol, an important fragrant constituent of patchouli oil, from (+)-camphor, that onetime important natural product which was employed as a plasticiser for nitrocellulose (itself a semi-synthetic polymer), was complicated by structural revision of the sesquiterpene alcohol. Dihydrocarvone (14) obtained by saturation of the ring double bond in carvone, a major constituent of oil of spearmint has been employed for two very different sesquiterpenes, the ketone campherenone (15) and the alcohol, occidentalol (16). In the first case an enol acetate was converted to a bicyclic intermediate by earlier established methodology and the route emulated a plausible biogenetic sequence giving racemic campherenone (ref.12) as shown. Any chirality in (14) is apparently lost. 

Holton s plan for the synthesis of the ab ring system of taxanes e.g. 83) involves fragmentation of an easily accessible tricyclic compound derived from patchouli alcohol. Hydroxy-directed epoxidation of the tertiary alcohol (84) (from patchino 90) gives an unstable substance which undergoes gmentation in situ to provide the keto alcohol (85 Scheme 29). 

A full report on the short stereocontrolled synthesis of racemic patchouli alcohol has been presented,362 the key steps of which are the Grignard addition of the magnesium derivative of the bromide (796) to the dienone (797) followed by an intramolecular Diels-Alder reaction. The preparation of the two enantiomers of... 

The final proof of the structure of a natural product after the latter has also been synthesized in the chemist s lab was, for a long time, common procedure [156], In a few cases, disagreement raised a few eyebrows. This was the case for patchouli alcohol and for a molecule called hexacyclinol [157]. Quinine is an example of the difficulties associated with the notion of a total synthesis. Shouts [35, 37,158] and murmurs [lib,159] have been expressed to comment on the wealth of total syntheses of natural products performed in the second half of the twentieth century. 

Intramolecular Diels-Alder reaction. Naf and Ohloff have reported a short stereoselective synthesis of racemic patchouli alcohol (3) that involves the intramolecular Diels-Alder reaction of (1) to give (2). This reaction was carried out in... 

The bicyclooctane core of the structure of patchouli alcohol suggests the Diels-Alder reaction as an approach to the synthesis and this was... 

In Figure 7.18, the starting material for the synthesis of patchouli alcohol is the ketone (P20.1). Explain how this can be formed by exhaustive base catalysed alkylation of phenol (Figure P20). 

The possibilities of using two-bond disconnections (i.e., the Diels-Alder transform) are easy to appreciate with respect to patchouli alcohol (50), a bridged tricyclic target. It is a historically amusing compound, as its initial (wrong) structure was proven by synthesis [163] (a proof that later had to be revised) [164] The correct structure of 50 possesses three... 

Scheme 6.47 Two-bond disconnection for a bicylization synthesis of patchouli alcohol...

The last one of the options shown in Scheme 6.47 has been realized [166], effecting a concise synthesis of patchouli alcohol, a highly valued fragrant material. 

Some details have appeared of the synthesis of seychellene involving Diels-Alder cyclization of (309) to (310) and (311) (3 1). A closely related route has been used to make patchouli alcohol. Heating the 1 1 mixture of diastereomers (312) at 280 °C with a little KOBu in decalin gave 30% of (313). In the absence of KOBu (314) was formed. The role of the base is unknown. ... 

The synthesis of natural products of ever increasing complexity has been a perennial task of preparative organic chemistry. However, over time, the motivation underlying this activity has changed in a characteristic manner. Up to the 1960s the synthesis of a natural product constituted the sole - and later on, the most important - proof of its structure. The reliability of such structural proof was not 100% - as can be seen from the structural assignment of patchouli-alcohol 1, a case in which the wrong structure has been proven by synthesis [1]. The correct structure was finally established by X-ray analysis [2]. 

One example of an early PGF synthesis is Robinson s 1917 landmark synthesis of tropinone 96 [80] (Scheme 13.15). By the combination of succinaldehyde 93, methylamine 94, and acetone dicarboxylic acid 95, tropinone resulted from what can be assumed to be a biomimetic process [81]. Another classic PGF synthesis is Danishefsky s 1968 preparation of patchouli alcohol (100) [82]. The atom-economical first step of this sequence, the Diels-Alder reaction of diene 97 and methyl vinyl ketone (98), is one of but not the only reason this example was chosen. Not to take away from the beauty of Danishefsky s synthesis, functionality contained within patchouli alcohol is minimal and as a result limited PG usage would be expected. Also, during the decades of the two syntheses the... 

The first synthesis of patchouli alcohol was actually directed towards an tv-patchoulane skeleton (A), the structure then believed to represent the natural product. It was only by a fortuitous rearrangement during the final stages of the synthesis that Buchi arrived at patchouli... 

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